TY - JOUR
T1 - Oxidative stress causes bone loss in estrogen-deficient mice through enhanced bone marrow dendritic cell activation
AU - Grassi, Francesco
AU - Tell, Gianluca
AU - Robbie-Ryan, Michaela
AU - Gao, Yuhao
AU - Terauchi, Masakazu
AU - Yang, Xiaoying
AU - Romanello, Milena
AU - Jones, Dean P.
AU - Weitzmann, M. Neale
AU - Pacifici, Roberto
PY - 2007/9/18
Y1 - 2007/9/18
N2 - Increased production of tumor necrosis factor α (TNF) in the bone marrow (BM) in response to both oxidative stress and T cell activation contributes to the bone loss induced by estrogen deficiency, but it is presently unknown whether oxidative stress causes bone loss through T cells. Here we show that ovariectomy causes an accumulation in the BM of reactive oxygen species, which leads to increased production of TNF by activated T cells through upregulation of the costimulatory molecule CD80 on dendritic cells. Accordingly, bone loss is prevented by treatment of ovariectomized mice with either antioxidants or CTLA4-Ig, an inhibitor of the CD80/CD28 pathway. In summary, reactive oxygen species accumulation in the BM is an upstream consequence of ovariectomy that leads to bone loss by activating T cells through enhanced activity of BM dendritic cells, and these findings suggest that the CD80/CD28 pathway may represent a therapeutic target for postmenopausal bone loss.
AB - Increased production of tumor necrosis factor α (TNF) in the bone marrow (BM) in response to both oxidative stress and T cell activation contributes to the bone loss induced by estrogen deficiency, but it is presently unknown whether oxidative stress causes bone loss through T cells. Here we show that ovariectomy causes an accumulation in the BM of reactive oxygen species, which leads to increased production of TNF by activated T cells through upregulation of the costimulatory molecule CD80 on dendritic cells. Accordingly, bone loss is prevented by treatment of ovariectomized mice with either antioxidants or CTLA4-Ig, an inhibitor of the CD80/CD28 pathway. In summary, reactive oxygen species accumulation in the BM is an upstream consequence of ovariectomy that leads to bone loss by activating T cells through enhanced activity of BM dendritic cells, and these findings suggest that the CD80/CD28 pathway may represent a therapeutic target for postmenopausal bone loss.
KW - CTLA-4Ig
KW - Osteoporosis
KW - Reactive oxygen species
KW - T cells
KW - Tumor necrosis factor
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U2 - 10.1073/pnas.0703610104
DO - 10.1073/pnas.0703610104
M3 - Article
C2 - 17848519
AN - SCOPUS:35448995621
VL - 104
SP - 15087
EP - 15092
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 38
ER -